Molecular pathogenesis of neurodegeneration and aging

My lab employs induced pluripotent stem cell (iPSC) neurons and glia derived from amyotrophic lateral sclerosis (ALS) patients to study the molecular pathogenesis of neurodegeneration and aging. Specifically, my lab wants to understand the subcellular processes involved in age-related and selective neurodegeneration observed in ALS. ALS is a fatal neurologic disease characterized by the progressive degeneration of motor neurons and interneurons in the brain and spinal cord. A unifying pathological feature of ALS is the cytoplasmic inclusion of nuclear proteins observed in post-mortem CNS tissue. Nuclear pore complexes (NPC) are channels that span the nuclear envelope and regulate the transport of proteins ≥40 kDa from passively entering or exiting the nucleus. NPC proteins are incredibly long-lived in post-mitotic cells and, consequently, NPC integrity is lost during normal aging thus resulting nuclear-cytoplasmic protein mislocalization. I have recently shown that a common ALS mutation, the C9ORF72 HRE, disrupts NPC function and nucleocytoplasmic trafficking. This impairs nuclear protein import and enhances cytoplasmic accumulation of predominantly nuclear proteins that are also shown to accumulate in the cytoplasm of neurons and glia of ALS patients. These are the first studies implicating NPC dysfunction in neurodegeneration and it is therefore enticing to postulate that NPC dysfunction or premature deterioration is a converging pathway in ALS pathogenesis. My lab utilizes iPSC models to study the mechanisms that underlie NPC and nucleocytoplasmic trafficking dysfunction in ALS and similar disorders that also exhibit aggregate pathology, including frontotemporal dementia (FTD) and traumatic brain injury. The goals of these studies are to uncover novel mechanisms that lead to selective neurodegeneration and to develop methods of intervention to prevent neural injury. Our long-term studies include: 1) in vivo validation of these mechanisms in existing neurodegenerative animal models and ALS patient tissue; 2) to identify intrinsic differences in the NPC composition of affected and unaffected neural subtypes in ALS; 3) develop models to link NPC/nucleocytoplasmic trafficking deficits to selective neurodegeneration; and 4) to rescue these trafficking defects and selective neurodegeneration in vivo with existing and novel therapeutics.